Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants
Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants
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DOI：
10.1128/aac.01540-10
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发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Mitsuya, Hiroaki
中科院分区：
文献类型：
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作者：
Ide, Kazuhiko;Aoki, Manabu;Mitsuya, Hiroaki
我们鉴定出了GRL-1388和-1398两种有效的非肽类人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（pi），它们含有一个双环P2功能片段，四氢吡喃-四氢呋喃（Tp-THF）。GRL-1388对多种耐药HIV-1实验室毒株具有与darunavir （DRV）相同的抗药效果，50%有效浓度（EC(50)s）为2.6 ~ 32.6 nM。GRL-1398的EC(50)s为0.1 ~ 5.7 nM，对这些变异的抑制作用明显强于DRV。GRL-1388和-1398对多重pi耐药的临床HIV-1变异体（CLHIV-1MDR）也有效，EC(50)s范围分别为2.7 ~ 21.3 nM和0.3 ~ 4.8 nM。体外筛选的高度抗DRV的HIV-1变异对GRL-1398仍然敏感，EC50为21.9 nM，而对DRV的EC50为214.1 nM。当用GRL-1398选择HIV-1NL4-3时，出现了4个氨基酸取代-亮氨酸到苯丙氨酸的位置10 (L10F), A28S， L33F和m46i，最终使病毒在bb0 1.0 μ M化合物存在下复制超过57周的选择。当选择10种不同的CLHIV-1MDR菌株的混合物时，GRL-1398比GRL-1388和DRV更明显地延迟了耐药变体的出现。模型分析表明，GRL-1398比GRL-1388和DRV具有更大的整体氢键和疏水相互作用，GRL-1388和-1398与蛋白酶活性位点氨基酸主链（Asp29和Asp30）存在氢键相互作用。目前的研究结果表明，GRL-1398可以作为治疗HIV-1感染的潜在药物进一步开发。
We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC(50)s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC(50)s of 0.1 to 5.7 nM. GRL-1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants (CLHIV-1MDR) with EC(50)s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selected in vitro remained susceptible to GRL-1398 with the EC50 of 21.9 nM, while the EC50 of DRV was 214.1 nM. When HIV-1NL4-3 was selected with GRL-1398, four amino acid substitutions-leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I-emerged, ultimately enabling the virus to replicate in the presence of > 1.0 mu M the compound beyond 57 weeks of selection. When a mixture of 10 different CLHIV-1MDR strains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection.